This is a Supplemental Grant Application requesting support for obtaining postmortem brain tissue from adult and teenage suicide victims and matched, normal control subjects from two brain collection programs: 1) Maryland Brain Collection Program (MBCP) and 2) Semmelweis University Budapest Brain Collection Program (SUBBCP). We understand that some funding may be available to support the acquisition of additional postmortem brain samples from the brain collection programs for the funded RO1 application and for studying the postmortem brain samples. The major objective of the proposed research in the funded competing continuation application is to study the cellular and molecular mechanisms associated with suicidal behavior in postmortem brain tissue from suicide victims and control subjects. In our application, we have proposed to study the PI and the Wnt signaling pathways, as well as the GABAergic system, in the postmortem brain of adult and teenage suicide victims and matched control subjects. More specifically, we will determine in Specific Aim 1 the enzyme PLD, IPs receptors, Ca2+independent PKC isozymes, and the transcription factor CREB and AP-1. In Specific Aim 2 we will determine the various components of the Wnt pathway, namely, GSK-3(3, (3-catenin, as well as calcineurin and the transcription factor NFAT, which are involved in the transcription of IPs receptors. In Specific Aim 3 we will study the GABA synthesizing enzymes, GADes and GAD67) as well as the key GABAA receptor subunits. The specific aim of the supplemental application is to acquire additional well-characterized postmortem brain samples from the two brain collection programs mentioned above and to perform the above neurochemical studies on these samples. We expect to get brain samples from 15 additional suicide cases from the MBCP and 10 suicide cases from the SUBBCP and an equal number of control cases per year for the period of four years. This will allow us to increase our total sample size and the sample size of subgroups such as teenage and adult suicide, depressed suicide and non-depressed suicide (i.e., subjects with bipolar illness, schizophrenia and substance abuse) or teenage suicide with no history of mental disorders, and thus enhance the specificity and significance of our findings in relation to: a) suicide, adult vs. teenage and b) diagnoses - depression, bipolar illness, schizophrenia or substance abuse. [unreadable] [unreadable] [unreadable]